tbuckley/cabot-search huggingface dataset:
High NEK2 expression in myeloid progenitors suppresses T cell immunity in multiple myeloma
Authors: Yan Cheng, Fumou Sun, Daisy V. Alapat, Visanu Wanchai, David Mery, Wancheng Guo, Huojun Cao, Yuqi Zhu, Cody Ashby, Michael Anton Bauer, Intawat Nookaew, Eric R. Siegel, Jun Ying, Jin-Ran Chen, Dongzheng Gai, Bailu Peng, Hongwei Xu, Clyde Bailey, Samer Al Hadidi, Carolina Schinke, Sharmilan Thanendrarajan, Maurizio Zangari, Marta Chesi, P. Leif Bergsagel, Frits van Rhee, Siegfried Janz, Guido Tricot, John D. Shaughnessy, Fenghuang Zhan
Journal: Cell Reports Medicine (2023)

Multiple myeloma (MM) growth is supported by an immune-tolerant bone marrow microenvironment. Here, we find that loss of Never in mitosis gene A (NIMA)-related kinase 2 (NEK2) in tumor microenvironmental cells is associated with MM growth suppression. The absence of NEK2 leads to both fewer tumor-associated macrophages (TAMs) and inhibitory T cells. NEK2 expression in myeloid progenitor cells promotes the generation of functional TAMs when stimulated with MM conditional medium. Clinically, high NEK2 expression in MM cells is associated with increased CD8+ T effector memory cells, while low NEK2 is associated with an IFN-γ gene signature and activated T cell response. Inhibition of NEK2 upregulates PD-L1 expression in MM cells and myeloid cells. In a mouse model, the combination of NEK2 inhibitor INH154 with PD-L1 blockade effectively eliminates MM cells and prolongs survival. Our results provide strong evidence that NEK2 inhibition may overcome tumor immune escape and support its further clinical development.
Valuing the functionality of tropical ecosystems beyond carbon
Authors: Jesús Aguirre-Gutiérrez, Nicola Stevens, Erika Berenguer
Journal: Trends in Ecology & Evolution (2023)

Land-based carbon sequestration projects, such as tree planting, are a prominent strategy to offset carbon emissions. However, we risk reducing natural ecosystems to one metric – carbon. Emphasis on restoring ecosystems to balance ecosystem services, biodiversity conservation, and carbon sequestration is a more appropriate strategy to protect their functioning.
An early-life microbiota metabolite protects against obesity by regulating intestinal lipid metabolism
Authors: Catherine D. Shelton, Elizabeth Sing, Jessica Mo, Nicolas G. Shealy, Woongjae Yoo, Julia Thomas, Gillian N. Fitz, Pollyana R. Castro, Tara T. Hickman, Teresa P. Torres, Nora J. Foegeding, Jacob K. Zieba, M. Wade Calcutt, Simona G. Codreanu, Stacy D. Sherrod, John A. McLean, Sun H. Peck, Fan Yang, Nicholas O. Markham, Min Liu, Mariana X. Byndloss
Journal: Cell Host & Microbe (2023)

The mechanisms by which the early-life microbiota protects against environmental factors that promote childhood obesity remain largely unknown. Using a mouse model in which young mice are simultaneously exposed to antibiotics and a high-fat (HF) diet, we show that Lactobacillus species, predominant members of the small intestine (SI) microbiota, regulate intestinal epithelial cells (IECs) to limit diet-induced obesity during early life. A Lactobacillus-derived metabolite, phenyllactic acid (PLA), protects against metabolic dysfunction caused by early-life exposure to antibiotics and a HF diet by increasing the abundance of peroxisome proliferator-activated receptor γ (PPAR-γ) in SI IECs. Therefore, PLA is a microbiota-derived metabolite that activates protective pathways in the small intestinal epithelium to regulate intestinal lipid metabolism and prevent antibiotic-associated obesity during early life.
CEGA: a method for inferring natural selection by comparative population genomic analysis across species
Authors: Shilei Zhao, Lianjiang Chi, Hua Chen
Journal: Genome biology (2023)

We developed maximum likelihood method for detecting positive selection or balancing selection using multilocus or genomic polymorphism and divergence data from two species. The method is especially useful for investigating natural selection in noncoding regions. Simulations demonstrate that the method outperforms existing methods in detecting both positive and balancing selection. We apply the method to population genomic data from human and chimpanzee. The list of genes identified under selection in the noncoding regions is prominently enriched in pathways related to the brain and nervous system. Therefore, our method will serve as a useful tool for comparative population genomic analysis.
Deep (phospho)proteomics profiling of pre- treatment needle biopsies identifies signatures of treatment resistance in HER2+ breast cancer
Authors: Donna O. Debets, Kelly E. Stecker, Anastasia Piskopou, Marte C. Liefaard, Jelle Wesseling, Gabe S. Sonke, Esther H. Lips, Maarten Altelaar
Journal: Cell Reports Medicine (2023)

Patients with early-stage HER2-overexpressing breast cancer struggle with treatment resistance in 20%–40% of cases. More information is needed to predict HER2 therapy response and resistance in vivo. In this study, we perform (phospho)proteomics analysis of pre-treatment HER2+ needle biopsies of early-stage invasive breast cancer to identify molecular signatures predictive of treatment response to trastuzumab, pertuzumab, and chemotherapy. Our data show that accurate quantification of the estrogen receptor (ER) and HER2 biomarkers, combined with the assessment of associated biological features, has the potential to enable better treatment outcome prediction. In addition, we identify cellular mechanisms that potentially precondition tumors to resist therapy. We find proteins with expression changes that correlate with resistance and constitute to a strong predictive signature for treatment success in our patient cohort. Our results highlight the multifactorial nature of drug resistance in vivo and demonstrate the necessity of deep tumor profiling.
Pleconaril and ribavirin in new-onset type 1 diabetes: a phase 2 randomized trial
Authors: Lars Krogvold, Ida Maria Mynarek, Erica Ponzi, Freja Barrett Mørk, Trine Witzner Hessel, Trine Roald, Nina Lindblom, Jacob Westman, Peter Barker, Heikki Hyöty, Johnny Ludvigsson, Kristian F. Hanssen, Jesper Johannesen, Knut Dahl-Jørgensen
Journal: Nature Medicine (2023)

Abstract Previous studies showed a low-grade enterovirus infection in the pancreatic islets of patients with newly diagnosed type 1 diabetes (T1D). In the Diabetes Virus Detection (DiViD) Intervention, a phase 2, placebo-controlled, randomized, parallel group, double-blind trial, 96 children and adolescents (aged 6–15 years) with new-onset T1D received antiviral treatment with pleconaril and ribavirin ( n = 47) or placebo ( n = 49) for 6 months, with the aim of preserving β cell function. The primary endpoint was the mean stimulated C-peptide area under the curve (AUC) 12 months after the initiation of treatment (less than 3 weeks after diagnosis) using a mixed linear model. The model used longitudinal log-transformed serum C-peptide AUCs at baseline, at 3 months, 6 months and 1 year. The primary endpoint was met with the serum C-peptide AUC being higher in the pleconaril and ribavirin treatment group compared to the placebo group at 12 months (average marginal effect = 0.057 in the linear mixed model; 95% confidence interval = 0.004–0.11, P = 0.037). The treatment was well tolerated. The results show that antiviral treatment may preserve residual insulin production in children and adolescent with new-onset T1D. This provides a rationale for further evaluating antiviral strategies in the prevention and treatment of T1D. European Union Drug Regulating Authorities Clinical Trials identifier: 2015-003350-41 .
Ketogenesis promotes tolerance to Pseudomonas aeruginosa pulmonary infection
Authors: Kira L. Tomlinson, Ying-Tsun Chen, Alex Junker, AndreaCarola Urso, Tania Wong Fok Lung, Danielle Ahn, Casey E. Hofstaedter, Swikrity U. Baskota, Robert K. Ernst, Alice Prince, Sebastián A. Riquelme
Journal: Cell Metabolism (2023)

Pseudomonas aeruginosa is a common cause of pulmonary infection. As a Gram-negative pathogen, it can initiate a brisk and highly destructive inflammatory response; however, most hosts become tolerant to the bacterial burden, developing chronic infection. Using a murine model of pneumonia, we demonstrate that this shift from inflammation to disease tolerance is promoted by ketogenesis. In response to pulmonary infection, ketone bodies are generated in the liver and circulate to the lungs where they impose selection for P. aeruginosa strains unable to display surface lipopolysaccharide (LPS). Such keto-adapted LPS strains fail to activate glycolysis and tissue-damaging cytokines and, instead, facilitate mitochondrial catabolism of fats and oxidative phosphorylation (OXPHOS), which maintains airway homeostasis. Within the lung, P. aeruginosa exploits the host immunometabolite itaconate to further stimulate ketogenesis. This environment enables host-P. aeruginosa coexistence, supporting both pathoadaptive changes in the bacteria and the maintenance of respiratory integrity via OXPHOS.
Correction: Clinical impact of the genomic landscape and leukemogenic trajectories in non-intensively treated elderly acute myeloid leukemia patients
Authors: Ekaterina Jahn, Maral Saadati, Pierre Fenaux, Marco Gobbi, Gail J. Roboz, Lars Bullinger, Pavlo Lutsik, Anna Riedel, Christoph Plass, Nikolaus Jahn, Claudia Walter, Karlheinz Holzmann, Yong Hao, Sue Naim, Nicholas Schreck, Julia Krzykalla, Axel Benner, Harold N. Keer, Mohammad Azab, Konstanze Döhner, Hartmut Döhner
Journal: Leukemia (2023)
Profiling small RNAs in fecal immunochemical tests: is it possible?
Authors: Einar Birkeland, Giulio Ferrero, Barbara Pardini, Sinan U. Umu, Sonia Tarallo, Sara Bulfamante, Geir Hoff, Carlo Senore, Trine B Rounge, Alessio Naccarati
Journal: Molecular Cancer (2023)

Abstract Fecal microRNAs represent promising molecules with potential clinical interest as non-invasive diagnostic and prognostic biomarkers. Colorectal cancer (CRC) screening based on the fecal immunochemical test (FIT) is an effective tool for prevention of cancer development. However, due to the poor sensitivity of FIT especially for premalignant lesions, there is a need for implementation of complementary tests. Improving the identification of individuals who would benefit from further investigation with colonoscopy using molecular analysis, such as miRNA profiling of FIT samples, would be ideal due to their widespread use. In the present study, we assessed the feasibility of applying small RNA sequencing to measure human miRNAs in FIT leftover buffer in samples from two European screening populations. We showed robust detection of miRNAs with profiles similar to those obtained from specimens sampled using the established protocol of RNA stabilizing buffers, or in long-term archived samples. Detected miRNAs exhibited differential abundances for CRC, advanced adenoma, and control samples that were consistent for FIT and RNA-stabilizing buffers. Interestingly, the sequencing data also allowed for concomitant evaluation of small RNA-based microbial profiles. We demonstrated that it is possible to explore the human miRNome in FIT leftover samples across populations and envision that the analysis of small RNA biomarkers can complement the FIT in large scale screening settings.
Increased Cardiac Risk After a Second Malignant Neoplasm Among Childhood Cancer Survivors
Authors: Thibaud Charrier, Nadia Haddy, Boris Schwartz, Neige Journy, Brice Fresneau, Charlotte Demoor-Goldschmidt, Ibrahima Diallo, Aurore Surun, Isabelle Aerts, François Doz, Vincent Souchard, Giao Vu-Bezin, Anne Laprie, Sarah Lemler, Véronique Letort, Carole Rubino, Stéfania Chounta, Florent de Vathaire, Aurélien Latouche, Rodrigue S. Allodji
Journal: JACC CardioOncology (2023)

Childhood cancer survivors (CCSs) are at an elevated risk of developing both a second malignant neoplasm (SMN) and cardiac disease. The study sought to assess the excess of occurrence of cardiac disease after a SMN among CCSs. Analyses included 7,670 CCSs from the French Childhood Cancer Survivors Study cohort diagnosed between 1945 and 2000. To account for the time dependence of the occurrence of a SMN, we employed a landmark approach, considering an additive regression model for the cumulative incidence of cardiac disease. We estimated the effect of a SMN on the instantaneous risk of cardiac disease using a proportional cause-specific hazard model, considering a SMN as a time-dependent exposure. In both models, we adjusted for demographic and treatment information and considered death as a competing event. In 7,670 CCSs over a median follow-up of 30 years (IQR: 22-38 years), there were 378 cases of cardiac disease identified, of which 49 patients experienced a SMN. Patients who survived 25 years after their childhood cancer diagnosis and had a SMN in that time frame had a significantly increased cumulative incidence of cardiac disease, which was 3.8% (95% CI: 0.5% to 7.1%) higher compared with those without a SMN during this period. No SMN-induced excess of cardiac disease was observed at subsequent landmark times. SMNs were associated with a 2-fold increase (cause-specific HR: 2.0 95% CI: 1.4-2.8) of cardiac disease. The occurrence of a SMN among CCSs is associated with an increased risk of cardiac disease occurrence and risk at younger ages.
IgM antibodies against acetylated proteins as a possible starting point of the anti-modified protein antibody response in rheumatoid arthritis
Authors: Tineke J van Wesemael, Sanne Reijm, Atsushi Kawakami, Annemarie L Dorjée, Gerrie Stoeken, Takahiro Maeda, Shin-ya Kawashiri, Tom W J Huizinga, Mami Tamai, René E M Toes, Diane van der Woude
Journal: Annals of the Rheumatic Diseases (2023)

Rheumatoid arthritis (RA) is characterised by the presence of anti-modified protein antibodies (AMPA): anti-citrullinated protein antibodies (ACPA), anti-carbamylated protein antibodies (anti-CarP) and anti-acetylated protein antibodies (AAPA).These AMPA responses are specific for RA and have consistently been found to develop years before disease onset. 1 2 Most studies on AMPA in (pre-disease) RA are focused on IgG antibodies.However, IgM is the first isotype generated in (auto)antibody responses.It is unclear whether IgM autoimmunity differs Bibl.
Planetary care is as vital as healthcare
Authors: Fran Baum
Journal: BMJ (2023)

Planetary care is as vital as healthcareThe duty of care that health professionals have for their patients needs to be matched with a duty of care for the planet, argues Fran Baum Fran Baum professor and directorHow did we arrive at the position where we devote so many resources to healthcare and yet have totally dropped the ball on caring for our planet?If the planet were a person she would be assessed as being dangerously, even fatally, ill.
Engineered hydrogel reveals contribution of matrix mechanics to esophageal adenocarcinoma and identifies matrix-activated therapeutic targets
Authors: Ricardo Cruz-Acuña, Secunda W. Kariuki, Kensuke Sugiura, Spyros Karaiskos, Eleanor M. Plaster, Claudia Loebel, Gizem Efe, Tatiana Karakasheva, Joel T. Gabre, Jianhua Hu, Jason A. Burdick, Anil K. Rustgi
Journal: Journal of Clinical Investigation (2023)

Increased extracellular matrix (ECM) stiffness has been implicated in esophageal adenocarcinoma (EAC) progression, metastasis, and resistance to therapy. However, the underlying pro-tumorigenic pathways are yet to be defined. Additional work is needed to develop physiologically relevant in vitro 3D culture models that better recapitulate the human tumor microenvironment and can be used to dissect the contributions of matrix stiffness to EAC pathogenesis. Here, we describe a modular, tumor ECM-mimetic hydrogel platform with tunable mechanical properties, defined presentation of cell-adhesive ligands, and protease-dependent degradation that supports robust in vitro growth and expansion of patient-derived EAC 3D organoids (EAC PDOs). Hydrogel mechanical properties control EAC PDO formation, growth, proliferation, and activation of tumor-associated pathways that elicit stem-like properties in the cancer cells, as highlighted through in vitro and in vivo environments. We also demonstrate that the engineered hydrogel serves as a platform to identify potential therapeutic targets to disrupt the contribution of pro-tumorigenic matrix mechanics in EAC. Together, these studies show that an engineered PDO culture platform can be used to elucidate underlying matrix-mediated mechanisms of EAC, and inform the development of therapeutics that target ECM stiffness in EAC.
Novel function of MOTS-c in mitochondrial remodelling contributes to its antiviral role during HBV infection
Authors: Caorui Lin, Linjie Luo, Zhen Xun, Chenggong Zhu, Ying Huang, Yuchen Ye, Jiawei Zhang, Tianbin Chen, Songhang Wu, Fuguo Zhan, Bin Yang, Can Liu, Ning Ran, Qishui Ou
Journal: Gut (2023)

Hepatitis B virus (HBV) infection causes substantial harm to mitochondrial activity, which hinders the development of effective treatments for chronic hepatitis B (CHB). The discovery of the mitochondrial-derived short peptide MOTS-c, which possesses multiple bioactivities, offers a promising new approach in treating HBV infection. This study aims to explore the diagnostic and therapeutic potential of MOTS-c in HBV-related diseases and its molecular mechanism.
Prioritizing persons deprived of liberty in global guidelines for tuberculosis preventive treatment
Authors: Aditya Narayan, Argita D. Salindri, Salmaan Keshavjee, Monde Muyoyeta, Kavindhran Velen, Zulma V. Rueda, Julio Croda, Salome Charalambous, Alberto L. García-Basteiro, Sheela V. Shenoi, Crhistinne C. M. Gonçalves, Liliane Ferreira da Silva, Lia G. Possuelo, Sarita Aguirre, Gladys Estigarribia, Guillermo Sequera, Louis Grandjean, Lily Telisinghe, Michael E. Herce, Fernanda Dockhorn, Frederick L. Altice, Jason R. Andrews
Journal: PLoS Medicine (2023)

Persons deprived of liberty (PDLs) are disproportionately impacted by tuberculosis, with high incidence rates and often limited access to diagnostics, treatment, and preventive measures.• The World Health Organization (WHO) expanded its recommendations for tuberculosis preventive treatment (TPT) to many high-risk populations, but their guidance does not include PDL, and most low-and middle-income countries do not routinely provide TPT in prisons.• Recent studies demonstrate high acceptability and completion rates of short-course TPT regimens in jails and prisons; costs of these regimens have been markedly reduced
Canakinumab as Adjuvant Therapy in Patients With Completely Resected Non–Small-Cell Lung Cancer: Results From the CANOPY-A Double-Blind, Randomized Clinical Trial
Authors: Edward B. Garon, Shun Lu, Yasushi Goto, Pedro De Marchi, Luis Paz-Ares, David R. Spigel, Michael Thomas, James Chih-Hsin Yang, Andrea Ardizzoni, Fabrice Barlesi, Sergey Orlov, Hiroshige Yoshioka, Giannis Mountzios, Sadhvi Khanna, Claudia Bossen, Mariana Carbini, Sabine Turri, Andrea Myers, Byoung Chul Cho
Journal: Journal of Clinical Oncology (2023)

Adjuvant canakinumab did not increase disease-free survival in resected non–small-cell lung cancer.
Spatial transcriptomic analysis of virtual prostate biopsy reveals confounding effect of tissue heterogeneity on genomic signatures
Authors: Sandy Figiel, Wencheng Yin, Dimitrios Doultsinos, Andrew Erickson, Ninu Poulose, Reema Singh, Anette Magnussen, Thineskrishna Anbarasan, Renuka Teague, Mengxiao He, Joakim Lundeberg, Massimo Loda, Clare Verrill, Richard Colling, Pelvender S. Gill, Richard J. Bryant, Freddie C. Hamdy, Dan J. Woodcock, Ian G. Mills, Olivier Cussenot, Alastair D. Lamb
Journal: Molecular Cancer (2023)

Abstract Genetic signatures have added a molecular dimension to prognostics and therapeutic decision-making. However, tumour heterogeneity in prostate cancer and current sampling methods could confound accurate assessment. Based on previously published spatial transcriptomic data from multifocal prostate cancer, we created virtual biopsy models that mimic conventional biopsy placement and core size. We then analysed the gene expression of different prognostic signatures (OncotypeDx®, Decipher®, Prostadiag®) using a step-wise approach with increasing resolution from pseudo-bulk analysis of the whole biopsy, to differentiation by tissue subtype (benign, stroma, tumour), followed by distinct tumour grade and finally clonal resolution. The gene expression profile of virtual tumour biopsies revealed clear differences between grade groups and tumour clones, compared to a benign control, which were not reflected in bulk analyses. This suggests that bulk analyses of whole biopsies or tumour-only areas, as used in clinical practice, may provide an inaccurate assessment of gene profiles. The type of tissue, the grade of the tumour and the clonal composition all influence the gene expression in a biopsy. Clinical decision making based on biopsy genomics should be made with caution while we await more precise targeting and cost-effective spatial analyses.
Mpox: The Reemergence of an Old Disease and Inequities
Authors: J.P. Thornhill, M. Gandhi, C. Orkin
Journal: Annual Review of Medicine (2023)

Mpox, previously known as monkeypox, is caused by an Orthopoxvirus related to the variola virus that causes smallpox. Prior to 2022, mpox was considered a zoonotic disease endemic to central and west Africa. Since May 2022, more than 86,000 cases of mpox from 110 countries have been identified across the world, predominantly in men who have sex with men, most often acquired through close physical contact or during sexual activity. The classical clinical presentation of mpox is a prodrome including fever, lethargy, and lymphadenopathy followed by a characteristic vesiculopustular rash. The recent 2022 outbreak included novel presentations of mpox with a predominance of anogenital lesions, mucosal lesions, and other features such as anorectal pain, proctitis, oropharyngeal lesions, tonsillitis, and multiphasic skin lesions. We describe the demographics and clinical spectrum of classical and novel mpox, outlining the potential complications and management.
Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial
Authors: Stephen A Harrison, Juan P Frias, Guy Neff, Gary A Abrams, K Jean Lucas, William Sanchez, Sudhanshu Gogia, Muhammed Y Sheikh, Cynthia Behling, Pierre Bedossa, Lan Shao, Doreen Chan, Erica Fong, Brittany de Temple, Reshma Shringarpure, Erik J Tillman, Timothy Rolph, Andrew Cheng, Kitty Yale
Journal: The Lancet. Gastroenterology & hepatology (2023)